Recurrent Nasal Polyposis and Bifid Epiglottis in a Child with Bardet–Biedl Syndrome Ciliopathy

Abstract

Bardet–Biedl syndrome (BBS) is a genetic disease caused by mutations of the BBS genes that encode proteins involved in cilia functioning. It can present with major and/or minor clinical manifestations, such as rod–cone dystrophy, polydactyly, obesity, speech delay, anosmia, congenital heart disease and genital and renal abnormalities. Diagnosis of this rare disease is based on clinical criteria and can be confirmed with molecular genetic testing. Although BBS is a ciliopathy, nasal polyposis has never before been reported in patients with this condition. This article presents the case of a 12-year-old male patient admitted with symptoms of retinopathy, development delay, anosmia, bifid epiglottis and recurrent nasal polyposis. After several clinical, imaging and genetic examinations, the patient was diagnosed with BBS. His nasal symptoms were treated with functional endoscopic sinus surgery and long-term antibiotic therapy, whereas courses of topical antibiotics as well as topical and systemic corticosteroids had no effect. As a conclusion, it is a rare case that presents new clinical manifestations (nasal polyps) that can be related to BBS and possible effective treatments.

1. Introduction

Bardet–Biedl syndrome (BBS) is a rare ciliopathy inherited through the autosomal recessive pattern. Its prevalence is approximately 1:160,000 births, and approximately 26 genes have been implicated in the pathogenesis of this disorder [1]. The major clinical signs and symptoms of the disease are cone–rod dystrophy (93%), polydactyly (65–81%), obesity (72–92%), learning disabilities (61%), genital abnormalities (59–98%) and renal abnormalities (53%). The minor clinical criteria refer to speech delay (54–81%), diabetes mellitus (6–48%), brachydactyly (6–100%), ataxia (40–86%), anosmia (60%) and cardiovascular involvement (7%) (

Table 1. Major and minor manifestations of Bardet–Biedl syndrome. Their presence or absence in the patient is indicated with the (+) or (−) symbols, respectively.

Major Symptoms	Minor Symptoms
Retinopathy (+) Polydactyly (+) Obesity (+) Learning disabilities (+) Genital abnormalities (+)	Speech disorders (+) Brachydactyly/syndactyly (−) Delayed development (+) Dental crowding (−) Craniofacial dysmorphism (−) Congenital heart disorders (+) Diabetes mellitus (+) Liver fibrosis (−) Hirschsprung’s disease (−) Anosmia (+)

). Due to the complexity of these clinical conditions, a diagnostic algorithm has been proposed that relies on the presence of either (1) four major criteria or (2) three major and two minor criteria for proper diagnosis [2].

2. Case Presentation

The patient was a 12-year-old boy admitted to the ear, nose and throat (ENT) department with chief complaints of chronic rhinitis and recurrent sinusitis. Associated symptoms were retinopathy, obesity, polydactyly of the one hand and minor speech and developmental delay. The patient also had a history of cardiovascular disorders and diabetes mellitus. He was taking propranolol (Inderal, AstraZeneca, Marousi, Greece) for arrythmias, but his diabetes was still well controlled with an appropriate diet. The initial ENT clinical and endoscopic examination revealed complete nasal obstruction caused by nasal polyposis. The morphology of the polyps was that of the typical edematous grape-like protrusions commonly seen in chronic rhinosinusitis. A sample of the nasal epithelium was sent for microscopic examination. The movement of the cilia was quite slow, and the nasal nitric oxide value was very low; these findings were compatible with the diagnosis of ciliopathy. Endoscopy of the larynx also revealed a bifid epiglottis (Figure 1). Due to the presence of the patient’s comorbidities, further examinations and genetic tests were performed.

A computed tomography (CT) scan revealed mucosal thickening and complete mucus retention in the sphenoid sinus, maxillary sinuses and most of the ethmoid air cells. Furthermore, the CT scan showed polypoid formations in both nasal cavities, hypertrophy of the nasopharynx and the presence of liquid within the mastoid air cells in the right and left sides (Figure 2 and Figure 3). The findings of the CT scan and endoscopic evaluation indicated sinusitis with nasal polyps, as well as chronic inflammation of mastoid air cells.

Genetic testing showed mutations of the BBS1 gene compatible with BBS in association with the patient’s symptomatology. Protein BBS1 is part of a group of proteins that control the function of cellular components called ‘cilia’. Cilia take part in cellular movement and many other cellular processes. More specifically, next-generation sequencing of an array of >250 genes revealed two BBS1 gene mutations in intron 1–2 (c.48-1G>A) and exon 9 (c.752deIT). When c.48-1G>A is in a heterozygous state in gene BBS1, it may alter the function of messenger ribonucleic acid. Moreover, it is considered pathogenic, based on criteria set by the American College of Medical Genetics and Genomics (ACMG). The mutation c.752deIT in heterozygosis in gene BBS1 produces the replacement of specific amino acids after 25 codons p. (Leu251Ginfs*25), which are responsible for protein synthesis. This mutation is also considered pathogenic according to ACMG criteria. According to current knowledge, gene BBS1 (KIAA1279) provides information for the synthesis of one specific protein that is found in all cells of the organism. No other known mutations were found in the whole exome sequencing, indicative of primary ciliary dyskinesia, a disease that is commonly associated with chronic rhinosinusitis.

Despite treatment with corticosteroids and antibiotics, the patient’s symptoms of anosmia (as reported by the patient and confirmed by ODOFIN, Screening 12 Sniffing Sticks, Burghart Messtechnik GmbH, Holm, Germany) and recurrent sinus infections persisted. A mini functional endoscopic sinus surgery (mini-FESS) was performed for the resection of nasal polyps and sinus drainage, followed by topical steroids with nasal rinses (Amp Pulmicort 0.5mgr, AstraZeneca, in 250 mL of sea salt wash solution). However, one year after the surgery, the patient’s symptoms relapsed, and a new CT scan again revealed the presence of nasal polyps obstructing both nasal cavities. Another mini-FESS (antrostomy and anterior ethmoidectomy) was performed with the aid of a navigator. Tympanostomy tubes were not inserted because there was no hearing loss or atelectasis of the tympanic membrane. A full house FESS or a reboot operation was avoided because of the age of the child but discussed as a possible option in the future. Nevertheless, four months after the operation, the patient’s symptoms recurred and Grade I and II polyps were noted in the nasal cavities. A broad-spectrum antibiotic was prescribed for two weeks, resulting in a significant improvement in the patient’s symptoms. The topical antibiotic, colistin, was avoided; the patient’s mother was reluctant regarding its application, as it had been ineffective in the past. A long-term, three-times-a-week schema of azithromycin was also prescribed. The patient’s condition has remained stable for the past two years, with only minor nasal obstructions and few instances of nasal secretion.

3. Discussion

Bardet–Biedl syndrome is a genetic disease with several systemic manifestations. It is considered a ciliopathy characterized mainly by cone–rod dystrophy, obesity, polydactyly, hypogonadism and renal disorders. Patients diagnosed with BBS may also present with minor clinical features, such as development and speech delay, anosmia and cardiac abnormalities [3,4]. In the present case, nasal polyposis and bifid epiglottis were associated with the presence of BBS despite rarely being seen in such patients.

To confirm the diagnosis, genetic testing is required to identify the mutations linked to the condition in association with the clinical criteria [5]. Moreover, it was of importance for the differential diagnosis of primary ciliary dyskinesia (PCD). In contrast to PCD, chronic sinusitis, and nasal polyposis in particular, is not a very common manifestation of all ciliary dysfunctions. Maybe this is the reason why this is the first case of nasal polyposis described for Bardet–Biedl syndrome.

In this study, the patient presented with almost all the major criteria and a few minor criteria, such as delayed development, diabetes, anosmia, cardiac abnormalities and speech disorders. Anosmia can be caused by sinusitis or due to the presence of BBS itself. In the present case, there was a rare and a new finding in a patient diagnosed with this type of syndrome: bifid epiglottis and nasal polyposis, respectively. Regarding our new finding, since this is an isolated case, this coexistence does not necessarily imply causation. It could be a very rare coincidence. Nonetheless, when children with BBS present with nasal symptoms, such as anosmia—which is not uncommon in BBS—a referral to otolaryngology is warranted to rule out sinusitis.

Bifid epiglottis is an uncommon clinical feature found in patients with BBS. In such cases, two separate epiglottic parts can be seen during laryngoscopy. According to the literature, only six children with BBS have to date been reported to also have bifid epiglottis. The rarity of this condition can be expected, as it is typically asymptomatic, making it difficult to recognize and link to the clinical findings of BBS.

What was even more interesting in the present case, however, was the presence of nasal polyposis and the polyps’ response to current treatment options. To the study’s authors’ knowledge, this condition has never been described before in this ciliopathy syndrome, although anosmia is commonly reported. The diagnosis of polyposis is relatively easy, and ciliopathy is considered a cause of chronic rhinosinusitis with nasal polyps. Systematic antibiotics may retain a partial though significant therapeutic effect in such patients. On the other hand, in the present case, topical and systemic corticosteroids and topical antibiotics did not result in symptomatic relief.

According to the current and newly presented clinical features of BBS, patients require a multifaceted approach from different specialties to relieve their symptoms (

Table 2. Take away messages.

Bardet–Biedl Syndrome (BBS) is a rare genetic ciliopathy, often diagnosed based on major clinical criteria such as cone–rod dystrophy, polydactyly, obesity, and renal abnormalities. Confirmed mutations in the BBS1 gene support the diagnosis alongside clinical criteria. In patients with BBS, an otolaryngology referral should be sought when anosmia or other nasal symptoms are being reported. This case report is unique in documenting recurrent nasal polyposis as a new manifestation of BBS. Nasal polyposis was managed with functional endoscopic sinus surgery (FESS) and long-term antibiotics, though the condition recurred. The findings suggest that systemic antibiotics may be more effective than topical and systemic corticosteroids and topical antibiotics for managing nasal symptoms in BBS-related nasal polyposis. As this is the first reported case of BBS with nasal polyps, additional cases are needed to better understand the role of steroid treatments and more extensive surgeries, such as full-house or reboot procedures.

). Hopefully, in the future, genetic-based treatment will be more specific and thus useful for these patients.

4. Conclusions

Bardet–Biedl syndrome is a rare clinical condition that requires the careful observation of an array of major and minor criteria for its diagnosis. In the case of findings such as retinopathy, obesity and learning and delayed development, as well as polydactyly and cardiac abnormalities, clinicians should include the differential diagnoses of genetic syndromes, such as BBS. Genetic testing is important for the confirmation of a diagnosis.

Nasal polyposis is a new manifestation presented in this case. Thus, in cases of nasal symptoms, an otolaryngology referral should be sought. In such cases, systematic antibiotics upon endoscopic surgery may be of value in contrast to topical and systemic corticosteroids and topical antibiotics.